Current Perspectives in Kidney Diseases. Группа авторов
by injured/activated cells with the aim of modulating the inflammatory response. The immune system is the main source of cytokines, but several other tissues are able to release them. During inflammatory processes, podocytes, TEC and renal endothelium can massively produce IL-18, IL-6 and chemokines such as IL-8 [9, 15]. Several studies have demonstrated the impact of these molecules in S-AKI prognosis; in particular, IL-6 and TNF correlated with AKI severity and with a worse patient survival [16].
Vasoactive Agents and Other Hormones. The release of all the above mentioned molecules coupled with organ dysfunction activates hormones and growth factors involved in homeostasis maintenance. These mediators could only partially counteract tissue injury and promote regeneration processes. However, the excess of signaling of specific stimuli can lead to the development of maladaptive responses. Examples include the massive production of nitric oxide (NO) that induces harmful NO-derived reactive oxygen species, the hyper-activation of the renin-angiotensin-aldosterone system (RAAS) and the sepsis-related catecholamine release that strongly contributes to microvascular vasoconstriction, thrombosis and/or hemorrhage [7, 17].
Immune Products, Activators of Complement and Coagulation Cascades. Cell injury exposes matrix proteins to bloodstream and activates the coagulation cascade. In parallel, complement system is activated by pathogens (mannose pathway), immune complexes (direct pathway) and by downregulation of complement-inhibiting proteins within injured cells (indirect-pathway). Moreover, the loss of glomerular filtration barrier causes proteinuria and exposes complement products to tubular brush border enzymes, thus inducing intra-luminal complement activation [18]. Additionally, activated immune cells release pathogen-killing factors (perforin, granzyme-B, etc.) able to worsen and to perpetuate cell injury [19].
Metabolites and Uremic Toxins. Uremic toxin is an omni-comprehensive term that includes all factors accumulating/upregulated during renal failure that cause any kind of tissue injury. Based on this definition, several molecules included in the previous categories can be defined as uremic toxins (i.e., some cytokines and RAAS). However, the largest part of uremic toxins is constituted by detrimental metabolic products, normally excreted by the kidney. p-Cresol sulfate and indoxyl sulfate are protein-bound metabolites not filtered by glomeruli and secreted by TEC; their accumulation in AKI and CKD is associated with several harmful effects such as endothelial injury and immune dysfunction [20].
Extracellular Vesicles (EV), Apoptotic Bodies and Other Cell Fragments. EV are membrane fragments actively produced to shuttle proteins, nucleic acids, lipids and other metabolites from an origin to a target cell [21]. EV play a key role in cell-to-cell communication processes and are classified as exosomes (30–120 nm in size and released by multi-vesicular bodies) or microvesicles (>120 nm and released by a membrane-sorting process), and they are involved in tissue repair and homeostasis. In the course of sepsis, a significant increase of plasma EV concentration is observed [22]. EV can be released by different cell types including monocytes, platelets and injured endothelial cells. The biological effects of EV may change in relation to the state of activation of the origin cell: this is of particular relevance in S-AKI patients in which plasma EV may represent not only a new biomarker for the early detection of disease, but also a key element in the pathogenic mechanisms of renal damage [22, 23]. Plasma EV are able to modulate NO and prostacyclin endothelial release, activate the coagulation cascade and cytokine production. EV isolated from septic animals and injected in healthy ones were able to induce the same functional and biological alterations observed in the course of the systemic inflammatory response, suggesting that EV can somehow transfer the septic disease to a healthy animal [24]. Moreover, sepsis-induced tissue injury promotes the passive release of other cell fragments such as apoptotic and necrotic bodies that have high DAMP concentrations. Several pathogens may also exploit EV to spread the infection or to transport PAMPs/toxins. Of interest, preliminary data from our research group demonstrated that despite their small size, EV are electrically charged and are not easily removed by standard diffusive and/or convective RRT.
Fluid Overload
Recent studies demonstrated the relevant role of fluid overload as AKI determinant. Indeed, a number of retrospective analysis investigating critically ill patients correlated central venous pressure and fluid overload with mortality and worse renal outcomes [25]. All these findings have been recently confirmed by a large multicenter, prospective, observational trial: authors found that the severity and speed of fluid accumulation are independent risk factors for ICU mortality [26].
New Biomarkers and Phenotypic Analysis of Cells in the Peripheral Blood
Diverse studies showed the association between serum levels of specific mediators and a worse outcome in septic patients. Soluble CD40-ligand, Fas-ligand and angiopoietin-2 are middle molecules involved in inflammation, coagulation and apoptotic cell damage that were found to be significantly increased in septic critically ill patients with a worse outcome [27]. In recent years, sepsis research also focused on the alterations of peripheral blood cells: it has been shown that a decreased expression of HLA-DR on monocytes is an indicator of immune paralysis and increased death risk [28]. Similarly, the variation of CD56+ Natural killer T cell count, the increase of CD4+CD25+Foxp3+ T regulatory cells, the decreased number of CD8+ T memory cells and the increased percentage of CD34+CD133+KDR+ endothelial progenitor cells in the peripheral blood have been associated with tissue injury and an increased mortality risk [28].
Extracorporeal Therapies in Patients with Sepsis-Associated AKI
Sepsis and AKI synergistically increase the mortality of ICU patients, and the short- and long-term mortality rates for S-AKI are still unacceptably high (about 50–70%) [29, 30]. Patients with S-AKI have increased mortality compared to non-septic AKI (across all stages of AKI) [31] and to patients with sepsis without AKI. Unfortunately, to date no effective therapy (excluding antimicrobial agents) has been shown to alter the outcome of S-AKI and its management is almost exclusively based on supportive therapies not always able to interfere with the mechanisms of tissue injury or the loss of immune homeostasis.
More than 2 decades ago, it was observed that RRT can remove inflammatory mediators from the plasma of septic patients and improve the pulmonary function [32]. Subsequently, clinical improvements, enhanced cytokine removal and a survival benefit with hemofiltration in septic patients have been reported [33]. Different studies showed that, excluding the absolute indications for RRT (fluid overload, metabolic acidosis, uremia, hyperkalemia and drug